The invention described herein relates to a novel olefination process which is useful for making certain itaconate and succinate derivatives.
It is desirable in a number of instances to be able to have an efficient and selective process, capable of scale-up, to make itaconate derivatives of formula (I), and/or succinate derivatives of formula (II) and/or (III): 
wherein xe2x80x9cR*xe2x80x9d is a sterically bulky group.
Of particular interest to us is the provision of compounds of the formula (IV), (V) and (VI), especially (IV) and (V): 
wherein R is aryl, C3-8 cycloalkyl, C1-10 alkyl, (aryl)C1-10 alkylene, (C3-8 cycloalkyl)C1-10 alkylene, heterocyclyl, (heterocyclyl)C1-10 alkylene, (aryl)C3-8 cycloalkylene, (C3-8 cycloalkyl)arylene or (C1-10 alkylaryl)C1-10 alkylene,
wherein xe2x80x9carylxe2x80x9d is a mono- or bicyclic partially or fully unsaturated carbocyclic ring system containing from 4 to 10 atoms, such as phenyl or naphthyl, or a partially or fully unsaturated mono- or bicyclic heterocyclic moiety having up to 10 atoms in the ring system and with up to 4 hetero-atoms in the said ring system each independently selected from N, O and S, said carbocyclic ring system and heterocyclic moiety being optionally substituted by one or more substituents each independently selected from halogen, NO2, NH2, CO2R9, phenyl, C1-6 alkyl(optionally substituted by one or more halogen), and C1-6 alkoxy(optionally substituted by one or more halogen), and xe2x80x9cheterocyclylxe2x80x9d is a 3- to 8-membered mono or bicyclic saturated heterocyclic group having from 1 to 4 ring hetero-atoms each independently selected from N, O and S, optionally substituted by one or more substituents each independently selected from halogen, NO2, NH2, CO2R9, phenyl, C1-6 alkyl(optionally substituted by one or more halogen), and C1-6 alkoxy(optionally substituted by one or more halogen);
R1 is C1-6 alkoxy,
R2 is OH or Oxe2x88x92M+;
R9 is H or C1-6 alkyl; and M+ is the cation of a metal such as sodium, lithium or potassium, or is a protonated amine moiety such as (mono-, di- or tri-C1-10 alkyl)ammonium, (mono-, di- or tri-C3-10 cycloalkyl)ammonium, (C1-10 alkyl)n1 (C3-10 cycloalkyl)n2ammonium, anilinium, benzylammonium, triethanolammonium, or (S)-xcex1-methylbenzylammonium, where n1 and n2 are each independently selected from 1 or 2 with the proviso that the sum of n1 and n2 is not greater than 3;
Alkyl groups, and groups containing alkyl moieties such as alkoxy and alkylene groups, can be straight chain or branched if the number of carbon atoms allows,
Halogen means fluorine, chlorine or bromine,
Cycloalkyl groups attached to an ammonium moiety can contain 1, 2, or 3 rings, where the number of carbon atoms allows, for example adamantanammonium.
Production of compounds related to (IV), (V) and (VI) has been disclosed previously, e.g. by Owton et al, in Synthetic Communications, 23(15), 2119-2125 (1993), M J Burk et al, Angew. Chem. Int. Edn. (Eng.) (1998) 37, 13/14, 1931-1933, Monsanto, U.S. Pat. No. 4,939,288, and by Chirotech Technology Ltd. in International Patent Application publication no. WO 99/31041. Known olefination reactions leading to systems related to (IV), generally result in poor E/Z selectivity, (for a review of the Stobbe condensation, see Org. React. 1951, 6, 1-73). Where selectivity has been controlled, however, for example by the use of phosphorus reagents, the substitution pattern is different from that required by us in formula (IV)(e.g. Monsanto, Owten, supra).
The products of the Owten chemistry are exemplified by compounds of the formula (VII): 
on which we attempted hydrolysis of the ethyl ester using conventional chemistry. In our hands this resulted in scrambling of the olefinic moiety resulting overall in a mixture of stereoisomers and regioisomers.
Use of the Monsanto chemistry gives products of the formula (VIII): 
which has the wrong substitution pattern for our requirements.
We have discovered a new and efficient olefination method which can be used to make compounds of formula (IV) in good yield and with good trans-selectivity, and which products can then be asymmetrically reduced to give compounds of formula (V) and (VI). The olefination is base-catalysed and can be used with enolisable aldehydes or aldehyde derivatives without significant amounts of self-condensation products. We also surprisingly observe no substantial double bond migration to give deconjugated isomers of (IV) under the basic conditions, which would afford other geometric and regio-isomers, which is another significant problem with similar prior art olefinations.
Our olefination system is thus particularly useful when highly selective production of the compounds (IV), (V) and/or (VI) is required, or where separation of (IV), (V) and/or (VI) and/or the respective isomers thereof, may be difficult or undesirable, such as in processing to make pharmaceutical products and regulatory starting materials for such products.
Thus, according to the present invention, there is provided a process for the preparation of compounds of formula (IV) as defined above, comprising reaction of an aldehyde of formula RCHO, or a protected derivative thereof such as a hemiacetal or adduct thereof such as a bisulphite, wherein R is as defined above, with a phosphorus compound of formula (IX): 
or a metal carboxylate salt thereof such as a sodium, lithium or potassium carboxylate salt thereof,
wherein R1 is as defined above, and
xe2x80x9cPxe2x80x9d is a phosphonate moiety of formula xe2x80x94P(O)(OR3)(OR4), wherein R3 and R4 are either each independently selected from H, C1-6 alkyl, benzyl and phenyl (optionally substituted by one or more C1-6 alkyl), or R3 and R4 taken together are C2-5 alkylene,
or xe2x80x9cPxe2x80x9d is a phosphorane moiety of formula xe2x80x94(PR5R6R7)+Xxe2x88x92 wherein R5, R6 and R7 are each independently selected from C1-6 alkyl and phenyl, and X is bromine, chlorine or iodine, in the presence of a sodium, lithium or potassium C1-C6 alkoxide base, in an inert solvent, and at a temperature of from xe2x88x9280xc2x0 C. to 20xc2x0 C.
Preferably the reaction time is less than 24 hours.
Preferably R is (aryl)C1-10 alkylene or (C3-8 cycloalkyl)C1-10 alkylene.
More preferably R is phenylethyl, cyclohexylethyl or (2-methyl-1,1xe2x80x2-biphenyl-4-yl)ethyl.
Preferably R1 is t-butoxy.
Preferably R2 is OH, Oxe2x88x92Li+, Oxe2x88x92Na+, Oxe2x88x92K+, Oxe2x88x92cyclohexylammonium+, Oxe2x88x92adamantanammonium+, Oxe2x88x92triethanolammonium+ or Oxe2x88x92(S)-xcex1-methylbenzylammonium+.
Preferably the olefination reaction is carried out using the aldehyde RCHO or the sodium bisulphite adduct thereof RCH(OH)SO3xe2x88x92Na+.
Preferably xe2x80x9cPxe2x80x9d is P(O)(OC2H5)2, P(O)(OCH2CH2O) or a triphenylphosphinium halide moiety.
More preferably P is P(O)(OC2H5)2.
Preferably the base is potassium t-butoxide, sodium t-butoxide or sodium methoxide.
When the base alkoxide and R1 are different there is a possibility of transesterification taking place during the olefination reaction. We have found that this apparently has no detrimental effect on the course of the reaction at the olefination centre, in terms of stereochemistry, and may not be important with respect to the use made of the product, e.g. if it is used as an intermediate and the R1 moiety is later removed, e.g. by displacement, hydrolysis or deprotection.
Preferably the olefination reaction solvent is anhydrous tetrahydrofuran, anhydrous toluene or R1H, where R1 takes the meaning as specified above with respect to the compounds of formulae (IV), (V) and (VI), or a mixture thereof.
More preferably the reaction solvent is selected from tetrahydrofuran and toluene when the aldehyde RCHO is used as a substrate, and selected from tetrahydrofuran/t-butanol and toluene when the bisulphite adduct is used as substrate.
Preferably the reaction is carried out at a temperature from xe2x88x9220xc2x0 C. to 10xc2x0 C.
More preferably the reaction is carried out at a temperature from xe2x88x9210xc2x0 C. to 10xc2x0 C.
Most preferably the reaction is carried out at a temperature from 0xc2x0 C. to 5xc2x00 C.
When the aldehyde RCHO is used as substrate, it is preferable to add the phosphorus compound to the base/solvent mixture, followed by addition of the aldehyde. Alternatively, the phosphorus compound and aldehyde are combined, then the base is added. A further alternative is to add the base to the phosphorus compound followed by addition of the aldehyde.
When the bisulphite is used as the substrate, it is preferable to add the base to a mixture of the bisulphite adduct and the phosphorus compound, or, alternatively, the bisulphite is added to a mixture of the phosphorus compound and the base.
xe2x80x98Bisulphitexe2x80x99 or xe2x80x98bisulphite adductxe2x80x99 is taken to mean an xcex1-hydroxysulphonate, which is the product of the reaction of an aldehyde with sodium, potassium or lithium bisulphite. Other suitable bisulphites are known in the art.
The skilled person will appreciate that the substrates, and starting material of formula (IX), can be obtained from commercial sources, or made by methods known in the art, e.g. by adaptation of the methods herein described in the sections below, and/or adaptation thereof, for example by methods known in the art. Suitable guides to synthesis, functional group transformations, use of protecting groups, etc. are found in standard organic chemistry textbooks, for example, xe2x80x9cComprehensive Organic Transformationsxe2x80x9d by R C Larock, VCH Publishers Inc. (1989), xe2x80x9cAdvanced Organic Chemistryxe2x80x9d by J March, Wiley Interscience (1985), xe2x80x9cDesigning Organic Synthesisxe2x80x9d by S Warren, Wiley Interscience (1978), xe2x80x9cOrganic Synthesisxe2x80x94The Disconnection Approachxe2x80x9d by S Warren, Wiley Interscience (1982), xe2x80x9cGuidebook to Organic Synthesisxe2x80x9d by R K Mackie and D M Smith, Longman (1982), xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T W Greene and PGM Wuts, John Wiley and Sons Inc. (1999), and P J Kocienski, in xe2x80x9cProtecting Groupsxe2x80x9d, Georg Thieme Vedag (1994), and any updated versions of said standard works.
The above olefination process is optionally followed by conversion of the product of formula (IV) where R2 is Oxe2x88x92M+ wherein M+ is a metal such as Na, Li or K, to a compound of formula (IV) where R2 is OH by treatment with a proton source, which may optionally be converted to a compound of formula (IV) wherein R2 is Oxe2x88x92M+(where M+ is a protonated amine moiety as previously defined), by treatment with a corresponding amine.
A further aspect of the invention is the asymmetric hydrogenation of itaconate compounds of the formula (IV) to give succinate compounds of the formula (V) or (VI).
Asymmetric hydrogenation of compounds of formula (IV) may be achieved in a multitude of ways, including methods known in the art. For example use may be made of catalytic hydrogenation using chiral rhodium or ruthenium complex of an optically active biphosphine or biphosphinite compound such as (4R,5R)-(xe2x88x92)-O-sopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane [(R,R)-DIOP], (R, R)-(xe2x88x92)-1,2-Bis[(O-methoxyphenyl)(phenyl)phosphino]ethane [(R,R)-DIPAMP], (xe2x88x92)-(R)-N,N-Dimethyl-1-((S)-1xe2x80x2,2-Bis(Diphenylphosphino)ferrocenyl)ethylamine [(R)-(S)-BPPFA], (xe2x88x92)-(2S,4S)-2-Diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonylpyrrolidine [(S,S)-BPPM], (2S,3S)-(xe2x88x92)-Bis(diphenylphosphino)butane [(S,S)-CHIRAPHOS], R-(+)-1,2-Bis(diphenylphosphino)propane [(R)-PROPHOS], (2R,3R)-(xe2x88x92)-2,3-Bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene [(R, R)-NORPHOS], (R)-(+)-2,2xe2x80x2-Bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl [(R)-BINAP], (R)-1,2-bis(diphenylphosphino)-1-cyclohexylethane [(R)-CYCPHOS], (2R,4R)-(+)-2,4-Bis(diphenylphosphino)pentane [(R,R)-BDPP], N-benzyl-(3R,4 R)-3,4-bis(diphenylphosphino)pyrrolidine [(R,R)-DEGPHOS], (xe2x88x92)-1,2-Bis((2R,5R)-2,5-dimethylphospholano)benzene [(R,R)-Me-DUPHOS], (-)-1,2-Bis((2R,5R)-2,5-diethylphospholano)benzene [(R,R)-Et-DUPHOS], N,Nxe2x80x2-bis[(R)-(+)-a-methylbenzyl]-N,Nxe2x80x2-bis(diphenylphosphino)ethylenediamine [(R)-PNNP], (R)-(xe2x88x92)-2,2xe2x80x2-bis(dicyclohexylphosphino)-6,6xe2x80x2-dimethyl-1,1xe2x80x2-biphenyl [(R)-BICHEP], (1R,2S,4R,5S)-2,5-dimethyl-7-phosphadicyclo[2.2.1]heptane [(R, S, R, S)-Me-PENNPHOS), (2S,2xe2x80x2S)-Bis(diphenylphosphino)-(1S,1xe2x80x2S)-bicyclopentane [(S,S)-BICP], 1,1xe2x80x2-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene [(S,S)-Et-FerroTANE], (R, R)-1,2-bis(di-t-butylmethylphosphino)methane [(R,R)-t-butyl-miniPHOS], (R)-(+)-2,2xe2x80x2-Bis(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl [(R)-tol-BINAP], (R)-(+)2-(Diphenylphosphino)-2xe2x80x2-methoxy-1,1xe2x80x2-binaphthyl [(R)-MOP], (R)-(+)-1-(2-Diphenyiphosphino-1-naphthyl)isoquinoline [(R)-QUINAP], Methyl xcex1-D-glucopyranoside-2,6-dibenzoate-3,4-di(bis(3,5-dimethylphenyl)phosphinite) (CARBOPHOS), (R)-(xe2x88x92)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine [(R)-(S)-JOSIPHOS], (R)-(xe2x88x92)-4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane [(R)-PHANEPHOS], (R)-(6,6xe2x80x2-Dimethoxybiphenyl-2,2-diyl)-bis(diphenylphosphine) [(R)-MeO-BIPHEP], ], (R)-(6-Chloro-6xe2x80x2-methoxybiphenyl-2,2-diyl)-bis(diphenylphosphine) [(R)-Cl-MeO-BIPHEP] or 2,2xe2x80x2-bis(diphenylphosphino)-4,4xe2x80x2, 6,6xe2x80x2-tetrakis(trifluoromethyl)-1,1xe2x80x2-biphenyl (BIFUP) which are well-known to the skilled chemist working in the asymmetric hydrogenation art.
It is to be appreciated that other examples include related structures, such as those with alternative alkyl substituents, and stereoisomers of the above-mentioned examples.
Some catalysts are mentioned in the Examples, and other suitable catalysts which may be useful are mentioned in the following publications and references therein, all of which are herein incorporated by reference in their entirety:
U.S. Pat. No. 4,939,288 (Monsanto); International Patent Application publication no. WO 98/02445 (Chiroscience Ltd);
International Patent Application publication no. WO 99/31041 (Chirotech Technology Ltd);
European Patent Application 0 673 911 Al (Takasago International Corporation);
International Patent Application publication no. WO 00/27855 (Chiroscience Technology Ltd);
X. Zhang, Enantiomer (1999), 4(6), 541;
H. Tye, JCS Perkin I, (2000) (3) 275-298;
J. M. Brown, Compr. Asymmetric Catal. I-III (1999), 1, 121-182;
M. J. Burk, Spec. Chem. (1998) 18(2) 58-59, 62;
T. Yamagishi, Organomet. News (1995) (4), 113-118;
J. P. Genet, ACS Symp. Ser. (1996) 641 (Reductions in Organic Synthesis), 31-51;
H. Kumobayashi, Recl. Trav. Chim. Pays-Bas (1996) 115(4) 201-210;
M. J. Burk et al, Pure Appl. Chem. (1996) 68(1) 3744;
H. Takaya et al, Catal. Asymm. Synth. (1993) 1-39;
S. Akutagawa, Chirality Ind. (1992) 325-339; A. Borner et al, Transition Met. Org. Synth. (1998) 2, 3-13;
D. G. Blackmond, CATTECH (1998) 2(1), 17-32;
R. Noyori, Acc. Chem. Res. (1997) 30(2) 97-102;
W. S. Knowles, Chem. Ind.(Dekker) (1996) 68(Catalysis of Organic Reactions) 141-152;
U. Behrens, Spec. Chem.(1996) 16(5) 174, 176-177;
R. Noyori, Acta Chem. Scand. (1996) 50(4), 380-390;
H. B. Kagan, Mec., Phys., Chim., Astron., (1996) 322(2) 131-143;
A. S. C. Chan et at, Chem. Ind.(Dekker) (1994) 53(Catalysis of Organic Reactions) 49-68;
K. Inoguchi et al, Synlett (1992) (3) 169-78;
G. Webb et at, Catal. Today (1992) 12(2-3) 319-337;
D. Arntz et al; Catal. Met. Complexes (1991) 12(Met. Promoted Sel. Org. Synth.) 161-189;
K. Harada, Asymmetric Synth. (1985) 5, 345-383; and
W. S. Knowles, Acc. Chem. Res.(1983) 16(3) 106-112.
The person skilled in the art will appreciate that the use of one enantiomer of such chiral catalysts will give one enantiomer (V) or (VI), and use of the other enantiomer will give the other enantiomer.
Some of the suitable catalysts may be generically defined by the formula P*-cat-P** wherein xe2x80x9ccatxe2x80x9d is a metal such as rhodium or ruthenium, and P* and P** each independently represents a chiral phosphine moiety, optionally conjoined.
Preferably the catalyst used for reduction of compounds of formula (IV) where R2 is Oxe2x88x92M+, is ruthenium based, such as ruthenium complexes of BINAP and derivatives thereof, such as [(S)-2,2xe2x80x2-bis(diphenylphosphino-1,1xe2x80x2-binaphthyl]chloro(p-cymene)ruthenium chloride.
Preferably the catalyst used for reduction of compounds of formula (IV) where R2 is OH, is rhodium-based, such as Rh-DUPHOS (1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene-(1,5-cyclooctadien)-rhodium (I) tetrafluoroborate) or Rh-Ferrotane (1,1xe2x80x2-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate).
Suitably the hydrogenation of the acid (IV, R2 is OH), can be carried out in the presence of a base such as sodium bicarbonate, cyclohexylamine, isopropylamine, t-butylamine, adamantanamine, or (S)-xcex1-methylbenzylamine. The hydrogenation can be carried out on a preformed salt (IV, R2 is Oxe2x88x92M+).
The reaction is suitably carried out in an inert solvent such as an aqueous C1-3 alcohol e.g. aqueous methanol, or C1-3 alcohol e.g. methanol. Other suitable inert solvents include, but is not limited to, tetrahydrofuran, ethyl acetate, tert-butyl methyl ether, xcex1, xcex1, xcex1-trifluorotoluene, methylene chloride or toluene. The reaction is carried out optionally at an elevated temperature, under a positive pressure of hydrogen.
Suitable temperatures for good yield and selectivity for the ruthenium-catalysed hydrogenation has been found to be approximately 60xc2x0 C., and for the rhodium-catalysed reactions at approximately 20xc2x0 C.
The skilled chemist will realise that suitable conditions for particular hydrogenations of compounds of formula (IV) can be found by routine modification of those mentioned herein.
A further aspect of the invention are novel compounds of formula (IV), (V) and (VI), and novel processes, including those mentioned in the Examples.
The invention is illustrated in the following Examples and Preparations section, but is not limited to these illustrations.

Triethylphosphonoacetate (12.0 Kg, 53.5 mol) was added over 30 minutes to a stirred solution of potassium tert-butoxide (7.20 Kg, 64.2 mol) in THF (118 liters), between 0 and 5xc2x0 C., under nitrogen. The mixture was warmed to 25-30xc2x0 C. where it was stirred for 1 hour and then added over 45 minutes to a solution of tert-butyl bromoacetate (11.5 Kg, 59.0 mol) in THF (28 liters), between 0 and 5xc2x0 C., under nitrogen. The mixture was stirred at 0-5xc2x0 C. for 1 hour and then demineralised water (6.1 liters) and ethanol (30 liters) were added. A solution of potassium hydroxide (4.2 Kg, 75.0 mol) in demineralised water (84 liters) was then added over 2 hours, between xe2x88x925 and 0xc2x0 C. The mixture was stirred at xe2x88x9210xc2x0 C. for 16 hours and then a solution of citric acid (16.5 Kg, 85.8 mol) in demineralised water (32 liters) was added. The mixture was concentrated in vacuo to a volume of 180 liters and then ethyl acetate (90 liters) was added. The organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (30 liters). The combined organic phases were washed with water (30 liters) and then stripped and replaced with cyclohexane by distillation at atmospheric pressure, at a constant volume of 72 liters. tert-Butylmethyl ether (18 liters) was added and the mixture was stirred at 20-25xc2x0 C. for 12 hours and then filtered. The residue was washed with a mixture of cyclohexane (16 liters) and ter-butylmethyl ether (3.6 liters) then dried in vacuo for 16 hours to give the title compound as a colourless solid (10.0 Kg, 60% yield, 98% pure by HPLC).
1H-NMR (CDCl3) xcex4: 4.20-4.10 (4H, m), 3.49-3.36 (1H, m), 3.00-2.85 (1H, m), 2.72-2.60 (1H, m), 1.20 (9H, s), 1.37-1.27 (6H, m)